ACOG PRACTICE BULLETIN Clinical Management Guidelines for Obstetrician–Gynecologists

Number 180, July 2017 (Replaces Practice Bulletin Number 137, August 2013) Gestational Mellitus mellitus (GDM) is one of the most common medical complications of pregnancy. However, debate continues to surround the diagnosis and treatment of GDM despite several recent large-scale studies address- ing these issues. The purposes of this document are the following: 1) provide a brief overview of the understanding of GDM, 2) review management guidelines that have been validated by appropriately conducted clinical research, and 3) identify gaps in current knowledge toward which future research can be directed.

population or racial or ethnic group. Caucasian women Background generally have the lowest rates of GDM. There is an Definition and Prevalence increased prevalence of GDM among Hispanic, African Gestational diabetes mellitus is a condition in which American, Native American, and Asian or Pacific Islander carbohydrate intolerance develops during pregnancy. women (3). Gestational diabetes also increases with the Gestational diabetes that is adequately controlled with- same risk factors seen for such as obesity out medication is often termed diet-controlled GDM or and increased age (4). With a greater prevalence of obe- class A1GDM. Gestational diabetes mellitus that requires sity and sedentary lifestyles, the prevalence of GDM medication to achieve euglycemia is often termed class among reproductive-aged women is increasing globally. A2GDM. Because many women do not receive screening for diabetes mellitus before pregnancy, it can be chal- Maternal and Fetal Complications lenging to distinguish GDM from preexisting diabetes. Women with GDM have a higher risk of developing However, it has been estimated that 6–9% of pregnan- preeclampsia (9.8% in those with a fasting cies are complicated by diabetes and that approximately less than 115 mg/dL and 18% in those with a fast- 90% of these cases represent women with GDM (1, 2). ing glucose greater than or equal to 115 mg/dL) and Additionally, the prevalence of GDM varies in direct undergoing a cesarean delivery (25% of women with proportion to the prevalence of type 2 diabetes in a given GDM who require medication and 17% of women with

Committee on Practice Bulletins—Obstetrics. This Practice Bulletin was developed by the American College of Obstetricians and Gynecologists Committee on Practice Bulletins—Obstetrics with the assistance of Aaron B. Caughey, MD, PhD. This information is designed as an educational resource to aid clinicians in providing obstetric and gynecologic care, and use of this information is voluntary. This information should not be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. It is not intended to substitute for the independent professional judgment of the treating clinician. Variations in practice may be warranted when, in the reasonable judgment of the treating clinician, such course of action is indicated by the condition of the patient, limitations of available resources, or advances in knowledge or technology. The American College of Obstetricians and Gynecologists reviews its publications regularly; however, its publications may not reflect the most recent evidence. Any updates to this document can be found on www.acog.org or by calling the ACOG Resource Center. While ACOG makes every effort to present accurate and reliable information, this publication is provided “as is” without any warranty of accuracy, reli- ability, or otherwise, either express or implied. ACOG does not guarantee, warrant, or endorse the products or services of any firm, organization, or person. Neither ACOG nor its officers, directors, members, employees, or agents will be liable for any loss, damage, or claim with respect to any liabilities, including direct, special, indirect, or consequential damages, incurred in connection with this publication or reliance on the information presented.

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Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. diet-controlled GDM underwent cesarean delivery ver- sus 9.5% of controls) (5, 6). Furthermore, women with Clinical Considerations and GDM have an increased risk of developing diabetes Recommendations (predominantly type 2 diabetes) later in life. It is esti- mated that up to 70% of women with GDM will develop How is gestational diabetes mellitus diabetes within 22–28 years after pregnancy (7–9). The diagnosed? progression to diabetes also is influenced by race, eth- All pregnant women should be screened for GDM with nicity, and obesity. For example, 60% of Latin American a laboratory-based screening test(s) using blood glucose women with GDM may develop type 2 diabetes within levels. Screening for GDM generally is performed at 5 years of their index pregnancy (10). 24–28 weeks of gestation (20). Early pregnancy screen- The offspring of women with GDM are at increased ing for undiagnosed type 2 diabetes, preferably at the risk of macrosomia, neonatal , hyperbili- initiation of prenatal care, is suggested in over- rubinemia, shoulder dystocia, and birth trauma. There weight and obese women with additional diabetic risk also is an increased risk of stillbirth, although how much factors, including those with a prior history of GDM this is related to glycemic control is debated (11). The (see Box 1) (17, 21). However, the best test for early results of the and Adverse Pregnancy GDM screening is not clear. The testing used to diag- Outcome study (HAPO), an international, multicenter nose type 2 diabetes in nonpregnant individuals (ie, a study, demonstrated a continuous relationship between fasting blood glucose followed by a 75-gm glucose load maternal glucose levels on each of the three values of and a 2-hour plasma glucose measurement) could be the 75-g, 2-hour oral (OGTT) and used for early pregnancy screening (22). Many obstetri- cesarean delivery, birth weight greater than the 90th cians or obstetric care providers use the two-step screen- percentile, clinical neonatal hypoglycemia, and fetal ing process that is used for GDM and start with a 50-g hyperinsulinemia (12). Other studies have demonstrated OGTT. The American Diabetes Association (ADA) has that fetal exposure to maternal diabetes contributes to noted that measurement of hemoglobin A1C also can be childhood and adult-onset obesity and diabetes in off- used, but it may not be suitable for use alone because of spring, which is independent of risks associated with decreased sensitivity compared with OGTT approaches obesity and genetic predisposition (13, 14). (21). Even if the results of early testing are negative, GDM screening still is recommended at 24–28 weeks Screening Practices, Diagnostic of gestation because of the large proportion of women Thresholds, and Treatment Benefits who had negative early pregnancy screening but who will go on to develop GDM (23). In women who have Historically, screening for GDM consisted of obtaining positive 50-g screening test results, but negative follow- the patient’s medical history and focused primarily on up test results early in pregnancy, it is common to use past obstetric outcomes and a family medical history of the follow-up test at 24–28 weeks of gestation without type 2 diabetes. A 1973 study proposed the use of the repeating the 50-g screening test. 50-g, 1-hour OGTT as a screening tool for GDM (15). The two-step approach to testing for GDM that is This test has since become widely accepted, and 95% of commonly used in the United States is based on first obstetricians in the United States use it as the tool for screening with the administration of a 50-g oral glucose universal screening of pregnant women (16, 17). solution followed by a 1-hour venous glucose determi- The use of historic factors (family or personal his- nation. Women whose glucose levels meet or exceed an tory of diabetes, previous adverse pregnancy outcome, institution’s screening threshold then undergo a 100-g, glycosuria, and obesity) to identify GDM will fail to 3-hour diagnostic OGTT. Gestational diabetes mellitus identify approximately one half of women with GDM is most often diagnosed in women who have two or more (18). Although certain factors place women at low risk abnormal values on the 3-hour OGTT. of GDM, it may not be cost effective to screen that group Institutional screening thresholds for the 1-hour of women with glucose tolerance testing. However, such glucose challenge vary from 130 mg/dL to 140 mg/dL, low-risk women represent only 10% of pregnant women with a range of sensitivities and specificities reported. and identifying those who should not be screened may However, there are no randomized trials that have add unnecessary complexity to the screening process examined whether one cutoff is more effective than oth- (19). Therefore, in 2014, the U.S. Preventive Services ers. Data regarding the ideal threshold value to screen Task Force made a recommendation to screen all preg- for gestational diabetes in order to improve pregnancy nant women for GDM at or beyond 24 weeks of gesta- outcomes also are insufficient, although standardization tion (17). of a screening threshold has been recommended (24).

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Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. For example, one cohort study showed that a value of 140 mg/dL had lower false-positive rates and improved Box 1. Screening Strategy for positive predictive values across various racial and Detecting Pregestational Diabetes or ethnic groups. This analysis also showed that sensitivi- Early Gestational Diabetes Mellitus ^ ties were only marginally improved when using lower thresholds (ie, 130 mg/dL and 135 mg/dL) (25). Using Consider testing in all women who are overweight or a higher standardized threshold of 140 mg/dL may obese (ie, have a body mass index greater than 25 or greater than 23 in Asian Americans) and have one lower the rate of false-positive screening test results and or more of the following additional risk factors: unnecessary administration of the 3-hour OGTTs, which has been shown to be associated with increased mater- • Physical inactivity nal stress and dissatisfaction regarding the process of • First-degree relative with diabetes screening for and diagnosing GDM (26–28). However, • High-risk race or ethnicity (eg, African American, in the absence of clear evidence that supports one Latino, Native American, Asian American, Pacific cutoff value over another (ie, 130 mg/dL, 135 mg/dL, Islander) or 140 mg/dL) for the 1-hour glucose screening test, • Have previously given birth to an infant weighing obstetricians and obstetric care providers may select one 4,000g (approximately 9 lb) or more of these as a single consistent cutoff for their practice, • Previous gestational diabetes mellitus using factors such as community prevalence rates of • Hypertension (140/90 mm Hg or on therapy for GDM when making their decision. hypertension) Different cutoffs for the 3-hour OGTT also have • High-density lipoprotein cholesterol level less than been proposed. Table 1 (20, 21) lists the diagnostic 35 mg/dL (0.90 mmol/L), a triglyceride level greater thresholds established for the 3-hour OGTT by the than 250 mg/dL (2.82 mmol/L) National Diabetes Data Group and by Carpenter and • Women with polycystic ovarian syndrome Coustan, with the latter using lower thresholds that subsequently result in higher rates of GDM diagnosis • A1C greater than or equal to 5.7%, impaired glucose tolerance, or impaired fasting glucose on previous (21). In the absence of clear comparative trials, one set testing of diagnostic criteria for the 3-hour OGTT cannot be clearly recommended over the other. For example, in a • Other clinical conditions associated with resistance (eg, prepregnancy body mass index greater cross-sectional study that compared the two sets of crite- than 40 kg/m2, acanthosis nigricans) ria in more than 26,000 women found that the diagnosis of GDM increased on average by 50% with the use of • History of cardiovascular disease the Carpenter and Coustan thresholds (29). However, a If pregestational or gestational diabetes mellitus is not study that examined the clinical outcomes showed that diagnosed, blood glucose testing should be repeated at the women in whom GDM would have been incremen- 24–28 weeks of gestation. tally diagnosed by the Carpenter and Coustan criteria Adapted with permission from the American Diabetes Association. alone had higher rates of perinatal complications than the Classification and Diagnosis of Diabetes. Diabetes Care 2017;40 women with values below these diagnostic thresholds (Suppl. 1):S11–S24. Copyright 2017 American Diabetes Association. (30). Women who have even one abnormal value on the

Table 1. Proposed Diagnostic Criteria for Gestational Diabetes Mellitus* ^

Plasma or Serum Glucose Plasma Level Level Carpenter and National Diabetes Coustan Conversion Data Group Conversion Status mg/dL mmol/L mg/dL mmol/L Fasting 95 5.3 105 5.8 1 hour 180 10.0 190 10.6 2 hours 155 8.6 165 9.2 3 hours 140 7.8 145 8.0 *A diagnosis generally requires that two or more thresholds be met or exceeded, although some clinicians choose to use just one elevated value. Adapted with permission from the American Diabetes Association. Classification and Diagnosis of Diabetes. Diabetes Care 2017;40 (Suppl. 1):S11–S24. Copyright 2017 American Diabetes Association.

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Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 100-g 3-hour OGTT have a significantly increased risk of significant improvements in maternal or newborn out- adverse perinatal outcomes compared with women with comes and highlighted the significant increase in health GDM. Thus, one elevated value, as opposed to two, may care costs that would result (24). Additionally, a 2015 be used for the diagnosis of GDM (31). Cochrane review supported that no specific screening Given the benefits of standardization, practitioners strategy has been shown to be optimal (35). In light and institutions should select a single set of diagnostic of this, the American College of Obstetricians and criteria, either plasma or serum glucose levels desig- Gynecologists (ACOG) supports the two-step process nated by the Carpenter and Coustan criteria or the and recommends that implications of suggested changes plasma levels established by the National Diabetes Data be studied before they are proposed at a national level. Group, for consistent use within their patient popula- However, individual practices and institutions may tions. Considerations for selection of one set of diag- choose to use the IADPSG’s recommendation, if appro- nostic criteria over the other could include, but are not priate, for the population they serve. limited to, the baseline prevalence of diabetes in their specific communities and the availability of resources What are the benefits of treating gestational to appropriately manage women in whom GDM will diabetes mellitus? be diagnosed by any given protocol. This approach, although imperfect, avoids establishment of a single set The 2005 Australian Carbohydrate Intolerance Study of diagnostic criteria across all populations based on in Pregnant Women trial, the first large-scale (1,000 expert opinion alone. women), randomized treatment trial for GDM (36) A one-step approach to establishing the diagnosis found the treatment was associated with a significant of GDM using a 75-g, 2-hour OGTT has been used reduction in the rate of the primary outcome, a compos- and promoted by other organizations. For example, in ite of serious newborn complications (perinatal death, 2010, the International Association of Diabetes and shoulder dystocia, and birth trauma, including fracture Pregnancy Study Group (IADPSG) recommended that or nerve palsy). Treatment also reduced preeclampsia a universal 75-g, 2-hour OGTT be performed during (from 18% to 12%) as well as reduced the frequency of pregnancy and that the diagnosis of GDM be established infants who were large for gestational age (LGA) (from when any single threshold value was met or exceeded 22% to 13%) and who had a birth weight greater than (fasting value, 92 mg/dL; 1-hour value, 180 mg/dL; 4,000 g (from 21% to 10%). A subsequent random- or 2-hour value, 153 mg/dL) (32). Overall, using the ized, multicenter treatment trial of 958 women with proposed IADPSG criteria would identify approxi- mild GDM conducted in the United States found that, mately 18% of pregnant women in the United States although there were no differences in the frequency of as having GDM; in some subpopulations, the propor- the primary composite outcome (perinatal death, neo- tion of women in whom GDM is diagnosed would be natal hypoglycemia, elevated umbilical cord C-peptide even higher. In 2011, the ADA endorsed these criteria level, and birth trauma), several significant differences while acknowledging that adopting these cutoffs would in secondary outcomes were observed with treatment, significantly increase the prevalence of GDM (33). including a lower frequency of LGA infants, lower fre- The additional women in whom GDM would be diag- quency of birth weight exceeding 4,000 g, and reduced nosed may be at a lower risk of adverse outcomes neonatal fat mass (37). Moreover, the rates of cesarean than and may not derive similar benefits from diag- delivery, shoulder dystocia, and hypertensive disorders nosis and treatment as women in whom GDM was were significantly reduced in women who were treated diagnosed by traditional criteria (34). As of 2017, the for GDM. A U.S. Preventive Services Task Force sys- ADA continues to recognize that there is an absence of tematic review underscored the demonstrated benefits clear evidence that supports the IADPSG-recommended of treating GDM and highlighted the reduced risks of approach versus the more traditional two-step screening preeclampsia, shoulder dystocia, and macrosomia (38). approach (21). The treatment in such studies has consisted of dietary In 2013, a Eunice Kennedy Shriver National Institute counseling with specific nutritional approaches (39–41) of Child Health and Human Development Consensus and exercise (42, 43). Based on this evidence, women in Development Conference on Diagnosing Gestational whom GDM is diagnosed should receive nutrition and Diabetes recommended that obstetricians and obstetric exercise counseling, and when this fails to adequately care providers continue to use a two-step approach to control glucose levels, medication should be used for screen for and diagnose GDM. The report underscored maternal and fetal benefit. It is important to note that the lack of evidence that the use of the one-step 75-g, in both trials described above, women with elevated 2-hour OGTT to diagnose GDM leads to clinically glucose values were treated with insulin, not oral agents,

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Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. when medical nutrition treatment did not control glucose What nonpharmacologic treatments are values. effective in managing gestational diabetes mellitus? How should blood glucose be monitored in a woman with gestational diabetes mellitus? Most commonly, GDM management begins with the nonpharmacologic approaches of dietary modifications, Once a woman with GDM begins nutrition therapy exercise, and glucose monitoring. A recent meta-analysis (dietary counseling), surveillance of blood glucose lev- of lifestyle modification trials in women with GDM els is required to confirm that glycemic control has been demonstrated a reduction in large-for-gestational-age established. However, there is insufficient evidence to neonates, macrosomia (defined as 4,000 g or more), and define the optimal frequency of blood glucose testing neonatal fat mass in neonates born to women random- in women with GDM. Based on the data available, the ized to lifestyle interventions (50). Additionally, women general recommendation is for daily glucose monitoring randomized to the lifestyle interventions were more four times a day, once after fasting and again after each likely to meet postpartum wieght goals 1 year after preg- meal. nancy. Despite these promising findings, the specific Mean fasting glucose values may be useful for managing diabetes in pregnant women because they are dietary and exercise approaches are less well studied. predictive of increased neonatal fat mass in the women’s The goal of medical nutrition therapy in women offspring. Neonatal fat mass has been shown to be with GDM is to achieve normal blood glucose levels, associated with the development of childhood obe- prevent ketosis, provide adequate weight gain, and sity and diabetes (44). Another study, a randomized contribute to appropriate fetal growth and develop- controlled trial that compared the value of prepran- ment. The ADA recommends nutritional counseling by dial versus postprandial measurements for blood glu- a registered dietitian and development of a personal- cose monitoring of women with GDM, showed that use ized nutrition plan based on the individual’s body mass of the 1-hour postprandial measurement was associated index for all patients with GDM (20). In some clinical with better glycemic control, a lower incidence of LGA settings in which a dietitian is not readily available, a infants, and lower rates of cesarean delivery for cepha- clinician should be able to provide recommendations to lopelvic disproportion (45). Given this evidence, fasting the patient based on three major nutritional components: and postprandial values should be used for monitor- 1) caloric allotment, 2) carbohydrate intake, and 3) ing blood glucose in women with GDM. Assessment of caloric distribution. postprandial blood glucose can be undertaken at either A diet composed of 50–60% carbohydrates often 1 hour or 2 hours after meals. No study to date has will result in excessive weight gain and postpran- demonstrated the superiority of either approach (46–48), dial hyperglycemia. Therefore, it has been suggested and this may be because postprandial glucose peaks that carbohydrate intake be limited to 33–40% of at approximately 90 minutes, between the two time calories, with the remaining calories divided between points (49). protein (20%) and fat (40%) (51); however, the actu- Once the patient’s glucose levels are well controlled al dietary composition that optimizes perinatal out- by diet, the frequency of glucose monitoring may be comes is unknown. For example, a randomized trial of modified depending on gestational age, overall concerns 99 women with GDM that compared a low-glycemic for adherence, and likely need for future adjustments to index nutrition plan with a conventional high-fiber diet care. It is unusual to recommend obtaining fewer than found that both produced similar pregnancy outcomes two measurements per day. (41). A small, recent randomized trial demonstrated In addition, no controlled trials have been per- that women with GDM randomized to a complex car- formed to identify optimal glycemic targets. The ADA bohydrate diet had lower fasting glucose values as and ACOG recommend that fasting or preprandial compared with those on a conventional diet (52). Given blood glucose values be below 95 mg/dL and post- these findings and the results of other treatment trials, prandial blood glucose values be below 140 mg/dL at complex carbohydrates are recommended over simple 1 hour or 120 mg/dL at 2 hours to reduce the risk of carbohydrates because they are digested more slowly, macrosomia (20). Generally, these values are reviewed are less likely to produce significant postprandial hyper- weekly; however, when there are many abnormal val- glycemia, and potentially reduce (40). ues, more frequent review is common. Alternatively, There is little evidence evaluating or supporting differ- with stable, normal values, less frequent review is ent dietary approaches to the treatment of GDM (39). acceptable. In practice, three meals and two to three snacks are

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Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. recommended to distribute carbohydrate intake and to only elevated fasting values, nighttime administration of reduce postprandial glucose fluctuations. intermediate-acting insulin, such as NPH insulin, may be Although there are multiple randomized trials that adequate. Similarly, in women with elevated values only have examined exercise and lifestyle interventions in for breakfast postprandial, short-acting insulin before adults with diabetes who are not pregnant, there are breakfast may be the only insulin needed. Regardless few published exercise trials in women with GDM. of the starting dosage, subsequent dosage adjustments Even though most of these published trials have small should be individualized according to the woman’s sample sizes, they do appear to show improvement monitored blood glucose levels at particular times of in glucose levels (42, 53–56). In adults with diabetes the day. For long-acting and intermediate-acting insulin, who are not pregnant, exercise—particularly weight NPH insulin has been the mainstay, but more recently training—increases lean muscle mass and improves tis- insulin glargine and insulin detemir have been described sue sensitivity to insulin. In overweight or obese women for long-acting use (59–61). For short-acting insulin, with GDM, exercise also may be able to improve glyce- insulin analogues—including insulin lispro and insulin mic control. Therefore, a moderate exercise program is aspart—have been used in pregnancy, and these insulin recommended as part of the treatment plan for women analogues do not cross the placenta. Insulin lispro and with GDM (20). Such a plan should mirror diabetes insulin aspart should be used preferentially over regular care in general, and women with GDM should aim for insulin because both have a more rapid onset of action, 30 minutes of moderate-intensity aerobic exercise at enabling the patient to administer her insulin right at least 5 days a week or a minimum of 150 minutes the time of a meal rather than 10–15 minutes before an per week (33). Simple exercise such as walking for anticipated meal. This provides better glycemic control 10–15 minutes after each meal can lead to improved and helps avoid hypoglycemic episodes from errors in glycemic control and is commonly recommended (57). timing (62, 63) (Table 2).

What pharmacologic treatments are effective Oral Antidiabetic Medications in managing gestational diabetes mellitus? Oral antidiabetic medications (eg, metformin and gly- buride) increasingly are being used among women with Pharmacologic treatment is recommended when target GDM, despite the fact that they have not been approved glucose levels cannot be consistently achieved through by the U.S. Food and Drug Administration for this indi- nutrition therapy and exercise. However, a system- cation (64) and even though insulin continues to be the atic review found no conclusive evidence for a spe- ADA-recommended first-line therapy (20). cific threshold value at which medical therapy should Metformin is a biguanide that inhibits hepatic be started (58). Insulin historically has been considered gluconeogenesis and glucose absorption and stimu- the standard therapy for GDM management in cases lates glucose uptake in peripheral tissues. Historically, refractory to nutrition therapy and exercise and this has metformin primarily has been used in women with pre- continued to be reinforced by the ADA (20). gestational diabetes or those with polycystic ovary syn- Insulin, which does not cross the placenta, can drome and infertility. In women with polycystic ovary achieve tight metabolic control and traditionally has been added to nutrition therapy if fasting blood glucose levels consistently are greater than or equal to 95 mg/dL, Table 2. Action Profile of Commonly Used Insulin Agents ^ if 1-hour levels consistently are greater than or equal to 140 mg/dL, or if 2-hour levels consistently are greater Onset of Peak of Duration of Type Action Action (h) Action (h) than or equal to 120 mg/dL. These thresholds largely have been extrapolated from recommendations for man- Insulin lispro 1–15 min 1–2 4–5 aging pregnancy in women with preexisting diabetes. If Insulin aspart 1–15 min 1–2 4–5 insulin is used, the typical starting total dosage is 0.7–1.0 Regular insulin 30–60 min 2–4 6–8 units/kg daily, given in divided doses. In cases in which Isophane insulin 1–3 h 5–7 13–18 fasting and postprandial hyperglycemia are present, suspension a regimen of multiple injections using long-acting or (NPH insulin) intermediate-acting insulin in combination with short- Insulin glargine 1–2 h No peak 24 acting insulin is administered. However, if there are Insulin detemir 1–3 h Minimal peak 18–26 only isolated abnormal values at a specific time of day, at 8–10 focusing the insulin regimen to correct the specific Modified from Gabbe SG, Graves CR. Management of diabetes mellitus compli- hyperglycemia is preferred. For example, in women with cating pregnancy. Obstet Gynecol 2003;102:857–68.

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Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. syndrome, metformin is often continued until the end or for those women whom the obstetricians or obstet- of the first trimester, despite only limited evidence to ric care providers believe the patients will be unable suggest that such use decreases the risks of adverse to safely administer insulin, metformin is a reasonable pregnancy outcomes, including first-trimester loss (65). second-line choice. Metformin crosses the placenta with levels that can Glyburide is a sulfonylurea that binds to pancreatic be as high as maternal concentrations. The long-term beta-cell adenosine triphosphate calcium channel recep- metabolic influence on the offspring is unknown (66); tors to increase insulin secretion and insulin sensitivity of however, one recent study found similar developmental peripheral tissues. It should not be used in patients who outcomes by 2 years of age (67). This concern about the report a sulfa allergy. Two recent meta-analyses have fetal exposure to metformin and the absence of long- demonstrated worse neonatal outcomes with glyburide term neonatal follow-up after in-utero metformin expo- compared with insulin in the treatment of GDM (70, 71). sure is one reason the ADA continues to recommend that Specifically, neonates who were given birth by women when pharmacologic treatment of GDM is indicated, treated with glyburide had higher rates of respiratory dis- insulin is considered the first-line treatment for diabetes tress syndrome, hypoglycemia, macrosomia, and birth in pregnancy (20). injury. These worse outcomes are despite the fact that In one large trial, 751 women with GDM were ran- individual trials comparing glyburide with insulin failed domly assigned to receive insulin therapy or metformin to show any significant difference in degree of glycemic (plus insulin if needed). Both groups experienced similar control (72–74). Observational studies have reported rates of a composite outcome of perinatal morbidity, higher rates of preeclampsia, hyperbilirubinemia, and consisting of neonatal hypoglycemia, respiratory dis- stillbirth with use of glyburide as compared with insulin, tress, need for phototherapy, birth trauma, prematurity, but many other outcomes have not been statistically sig- and low Apgar scores (68). In another prospective trial, nificantly different (64, 75–80). The common dosage of women randomized to metformin had lower mean glu- glyburide is 2.5–20 mg daily in divided doses, although cose levels, less gestational weight gain, and neonates pharmacokinetic studies during pregnancy indicate daily with lower rates of hypoglycemia than those randomized doses up to 30 mg may be necessary to achieve adequate to insulin (69). In a recent meta-analysis, the differences control (81). Additionally, 4–16% (or more) women between neonates delivered to women randomized to required the addition of insulin to maintain good glyce- metformin versus insulin were minimal. Interestingly, mic control when glyburide was used as initial treatment women randomized to metformin experienced a higher (72, 76, 82, 83). Despite the increased use of glyburide rate of preterm birth (risk ratio, 1.5), but a lower rate of over the past decade (64), the evidence indicates that gestational hypertension (risk ratio, 0.53) (70). Thus, glyburide treatment should not be recommended as a although metformin may be a reasonable second-line first-line pharmacologic treatment because, in most approach to treat gestational diabetes, it is important to studies, it does not yield equivalent outcomes to insulin. counsel women about the unusual finding of increased Concerns also have been raised about the safety of preterm birth, placental transfer of the drug, and lack oral antidiabetic agents during pregnancy. For example, of long-term data in exposed offspring. Additionally, in although an initial study that analyzed umbilical cord the aforementioned prospective trials, between 26% and blood revealed no detectable glyburide in exposed 46% of women who took metformin alone eventually pregnancies (72), a subsequent study demonstrated required insulin (68, 69). that glyburide does cross the placenta (81). As men- The dosage for metformin usually starts at 500 mg tioned previously, metformin also has been found to nightly for 1 week at initiation, then increases to 500 mg freely cross the placenta, and the fetus is exposed to twice daily. Because metformin generally is not used in concentrations similar to maternal levels (84). Theoretic patients with chronic renal disease, creatinine often is concerns include the potential effects of in utero met- checked at baseline to ensure adequate renal function. formin exposure on long-term glucose homeostasis of The most common adverse effects of metformin are developing offspring. It also is not yet known whether abdominal pain and diarrhea, which are minimized by oral antidiabetic medications affect the progression to slowly increasing the dosage. Such adverse effects were type 2 diabetes later in life in women who were treated reported in 2.5–45.7% of patients enrolled in studies during pregnancy. Although current data demonstrate no of metformin in pregnancy (70), and it is common to adverse short-term effects on maternal or neonatal health recommend taking the medication with meals to reduce from oral diabetic therapy during pregnancy, long-term symptoms. If higher doses are needed, the maximum outcomes are not yet available. Thus, health care provid- dose is usually 2,500–3,000 mg per day in two to three ers should counsel women of the limitations in safety divided doses. In women who decline insulin therapy data when prescribing oral agents to women with GDM.

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Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Is fetal assessment indicated in pregnancies believed to be of appropriate weight for gestational age complicated by gestational diabetes mellitus? were randomized at 38 weeks of gestation to induc- tion of labor within 1 week or expectant management, Antepartum fetal testing is recommended for patients there was no difference in cesarean delivery rates (89). with pregestational diabetes. Because the increased risk However, there was a smaller proportion of LGA infants of fetal demise in patients with pregestational diabetes in the induction group. Furthermore, a multiple time is related to suboptimal glycemic control, it would be series cohort study showed that there were no significant expected that women with GDM who have poor glyce- differences in either macrosomia or cesarean delivery mic control also would be at increased risk. Therefore, rates among women with insulin-treated GDM who fetal surveillance may be beneficial for women with underwent induction of labor at 38–39 weeks of gesta- GDM with poor glycemic control. Additionally, because tion when compared with expectantly managed historic those women who are treated medically with insulin or controls (90). Shoulder dystocia was experienced by oral agents had suboptimal glycemic control at some 10% of the expectant management group after more than time, fetal surveillance usually is recommended for these 40 weeks of gestation versus 1.4% in the group with patients as well (85). Antenatal fetal testing in women labor induction at 38–39 weeks of gestation. A systemat- with poorly controlled or medication-requiring GDM ic review later confirmed these findings (91). However, without other morbidities usually is initiated at 32 weeks a recent study that compared induction of labor before of gestation. If other factors associated with increased 40 weeks of gestation with expectant management dem- risk of adverse pregnancy outcome are present, it may onstrated a reduction in cesarean delivery among women be reasonable to start surveillance earlier in pregnancy. with GDM who were induced (92). A decision analysis Studies have not specifically demonstrated an demonstrated that delivery of women with GDM at increase in stillbirth with well-controlled A1GDM before 38 weeks or 39 weeks of gestation would reduce overall 40 weeks of gestation. Thus, antepartum fetal testing may perinatal mortality without increasing cesarean delivery not be necessary in these women. There is no consensus rates (93). Although persuasive, these data have not regarding antepartum fetal testing among women with been confirmed by large randomized trials. Therefore, well-controlled GDM who are not medically treated the timing of delivery in women with GDM that is (A1GDM). If antepartum testing is to be used in such controlled with only diet and exercise (A1GDM) should patients, it is generally started later than in women with not be before 39 weeks of gestation, unless otherwise A2GDM. The specific antepartum test and frequency indicated. In such women, expectant management up to of testing may be chosen according to local practice; 40 6/7 weeks of gestation in the setting of indicated however, because polyhydramnios can result from fetal antepartum testing is generally appropriate. For women hyperglycemia, it is common for clinicians to use testing with GDM that is well controlled by medications that incorporates serial measures of amniotic fluid. (A2GDM), delivery is recommended from 39 0/7 weeks to 39 6/7 weeks of gestation. What are delivery considerations in In contrast, expert opinion has supported earlier pregnancies complicated by gestational delivery for women with poorly controlled GDM (86, diabetes mellitus? 87). But clear guidance about the degree of glycemic control that necessitates earlier delivery is lacking, and Women with GDM with good glycemic control and no the recommendations about timing of delivery lack spe- other complications are commonly managed expectantly cific guidance as well (94). In light of this, consideration until term (86, 87). In most cases, women with good of timing should incorporate tradeoffs between the risks glycemic control who are receiving medical therapy of prematurity and the ongoing risks of stillbirth. In such do not require delivery before 39 weeks of gestation. a setting, delivery between 37 0/7 weeks and 38 6/7 The recent GINEXMAL trial of GDM-only patients weeks of gestation may be justified, but delivery in the randomized women to induction of labor at 38 weeks late preterm period from 34 0/7 weeks to 36 6/7 weeks of of gestation versus expectant management up to gestation should be reserved for those women who fail 41 weeks of gestation (88). Although the study did not in-hospital attempts to improve glycemic control or who achieve its intended sample size, there was no differ- have abnormal antepartum fetal testing. ence in cesarean delivery rates (12.6% versus 11.8%, Because macrosomia is distinctly more common P=.81) or many other outcomes. There was, however, a in women with GDM and because shoulder dystocia higher rate of hyperbilirubinemia in the induced group is more likely at any given fetal weight in pregnancies (10.0% versus 4.1%, P=.03). In a randomized trial in complicated by diabetes than in pregnancies not compli- which women with insulin-treated GDM and fetuses cated by diabetes (95–97), it is reasonable for clinicians

e24 Practice Bulletin Gestational Diabetes Mellitus OBSTETRICS & GYNECOLOGY

Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. to assess fetal growth by ultrasonography or by clinical How should women with a history of gesta- examination late in the third trimester to attempt to iden- tional diabetes mellitus be screened and tify macrosomia among women with GDM. However, counseled postpartum? data are insufficient to determine whether cesarean delivery should be performed to reduce the risk of birth Although the carbohydrate intolerance of GDM fre- trauma in cases of suspected macrosomia. Although the quently resolves after delivery, up to one third of use of ultrasonography to estimate fetal weight is com- affected women will have diabetes or impaired glucose mon, one recent study found that among cases of ultraso- metabolism at postpartum screening. It has been esti- nography-diagnosed LGA infants, only 22% were LGA mated that between 15% and 70% will develop diabe- at birth (98). Additionally, in women whose fetuses tes (predominantly type 2) later in life (9, 102–105). received an LGA diagnosis, the risk of cesarean delivery Another study showed that women with a history of was increased independent of actual birth weight. It has GDM have a sevenfold increased risk of developing been estimated that up to 588 cesarean deliveries would type 2 diabetes compared with women without a history be needed to prevent a single case of permanent brachial of GDM (106). Therefore, screening at 4–12 weeks post- plexus palsy for an estimated fetal weight of 4,500 g, partum is recommended for all women who had GDM to and up to 962 cesarean deliveries would be needed for identify women with diabetes, impaired fasting glucose an estimated fetal weight of 4,000 g (99, 100). Based on levels, or impaired glucose tolerance (IGT) (Fig. 1) (20). the available data, it is not possible to determine whether A fasting plasma and the 75-g, 2-hour OGTT the potential benefits of planned cesarean delivery at a have been used for diagnosing overt diabetes in the post- given estimated fetal weight are similar for women with partum period. Although the fasting plasma glucose test GDM and women with preexisting diabetes. Therefore, is easier to perform, it lacks sensitivity for detecting it appears reasonable to recommend that women with other forms of abnormal glucose metabolism. Results GDM should be counseled regarding the risks and bene- of the OGTT can confirm an impaired fasting glucose fits of a scheduled cesarean delivery when the estimated level and impaired glucose tolerance. Therefore, the fetal weight is 4,500 g or more (101). Fifth International Workshop on Gestational Diabetes

Gestational diabetes

FPG or 75-g, 2-hr OGTT at 4–12 weeks postpartum

FPG >125 mg/dL or FPG 100–125 mg/dL or FPG <100 mg/dL or 2-hr glucose >199 mg/dL 2-hr glucose 140–199 mg/dL 2-hr glucose <140 mg/dL

Diabetes mellitus Impaired fasting glucose or IGT or both Normal

Refer for Consider referral for management Assess glycemic status every 1–3 years Weight loss and physical activity Weight loss and physical activity counseling as needed counseling as needed Consider metformin if combined impaired fasting glucose and IGT Medical nutrition therapy Yearly assessment of glycemic status

Figure 1. Management of postpartum screening results. Abbreviations: FPG, fasting plasma glucose; OGTT, oral glucose tolerance test; IGT, impaired glucose tolerance. ^

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Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Mellitus recommends that women with GDM undergo a most studies, it does not yield equivalent outcomes 75-g, 2-hour OGTT in the postpartum period (107). This to insulin. usually should include a fasting plasma glucose as well. Health care providers should counsel women of the All women who had GDM should follow up with limitations in safety data when prescribing oral a primary care physician. Additionally, women with agents to women with GDM. impaired fasting glucose, IGT, or diabetes should be Women with GDM should be counseled regarding referred for preventive or medical therapy. Women with the risks and benefits of a scheduled cesarean deliv- impaired fasting glucose or IGT may respond to life- ery when the estimated fetal weight is 4,500 g or style modification and pharmacologic interventions to more. decrease incident diabetes. Women with frank diabetes benefit from ongoing intensive medical therapy. The The following recommendations and conclusions ADA and ACOG recommend repeat testing every 1–3 are based primarily on consensus and expert opin- years for women who had a pregnancy affected by GDM ion (Level C): and normal postpartum screening test results (20). For women who may have subsequent pregnancies, In the absence of clear evidence that supports one screening more frequently between pregnancies can cutoff value over another (ie, 130 mg/dL, 135 mg/ detect abnormal glucose metabolism before fertilization dL, or 140 mg/dL) for the 1-hour glucose screening and provides an opportunity to ensure prepregnancy test, obstetricians and obstetric care providers may glucose control (107). Women should be encouraged to select one of these as a single consistent cutoff for discuss their GDM history and need for screening with their practice, using factors such as community prev- their obstetricians or obstetric care providers. alence rates of GDM when making their decision. In the absence of clear comparative trials, one set of Summary of diagnostic criteria for the 3-hour OGTT cannot be clearly recommended over the other. Given the ben- Recommendations and efits of standardization, practitioners and institu- Conclusions tions should select a single set of diagnostic criteria, either plasma or serum glucose levels designated by The following recommendations and conclusions the Carpenter and Coustan criteria or the plasma are based on good and consistent scientific evi- levels established by the National Diabetes Data dence (Level A): Group, for consistent use within their patient popu- Women in whom GDM is diagnosed should receive lations. nutrition and exercise counseling, and when this Once a woman with GDM begins nutrition therapy fails to adequately control glucose levels, medica- (dietary counseling), surveillance of blood glucose tion should be used for maternal and fetal benefit. levels is required to confirm that glycemic control When pharmacologic treatment of GDM is indicat- has been established. ed, insulin is considered the first-line treatment for In practice, three meals and two to three snacks are diabetes in pregnancy. recommended to distribute carbohydrate intake and to reduce postprandial glucose fluctuations. The following recommendations and conclusions are based on limited or inconsistent scientific evi- Women with GDM should aim for 30 minutes of moderate-intensity aerobic exercise at least 5 days a dence (Level B): week or a minimum of 150 minutes per week. All pregnant women should be screened for GDM The timing of delivery in women with GDM that is with a laboratory-based screening test(s) using controlled with only diet and exercise (A1GDM) blood glucose levels. should not be before 39 weeks of gestation, unless In women who decline insulin therapy or for those otherwise indicated. In such women, expectant women whom the obstetrician or obstetric care pro- management up to 40 6/7 weeks of gestation in the vider believes the patient will be unable to safely setting of indicated antepartum testing is general- administer insulin, metformin is a reasonable sec- ly appropriate. ond-line choice. For women with GDM that is well controlled by Glyburide treatment should not be recommended as medications (A2GDM), delivery is recommended at a first-line pharmacologic treatment because, in 39 0/7 to 39 6/7 weeks of gestation.

e26 Practice Bulletin Gestational Diabetes Mellitus OBSTETRICS & GYNECOLOGY

Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Screening at 4–12 weeks postpartum is recom- 7. England LJ, Dietz PM, Njoroge T, Callaghan WM, Bruce C, Buus RM, et al. Preventing type 2 diabetes: mended for all women who had GDM to identify public health implications for women with a history women with diabetes, impaired fasting glucose lev- of gestational diabetes mellitus. Am J Obstet Gynecol els, or impaired glucose tolerance. Women with 2009;200:365.e1–8. (Level III) ^ impaired fasting glucose, IGT, or diabetes should be 8. O’Sullivan JB. Body weight and subsequent diabetes referred for preventive or medical therapy. The mellitus. JAMA 1982;248:949–52. (Level II-3) ^ ADA and ACOG recommend repeat testing every 9. Kim C, Newton KM, Knopp RH. Gestational diabetes 1–3 years for women who had a pregnancy affected and the incidence of type 2 diabetes: a systematic review. by GDM and normal postpartum screening test Diabetes Care 2002;25:1862–8. (Systematic Review) ^ results. 10. Kjos SL, Peters RK, Xiang A, Henry OA, Montoro M, Buchanan TA. Predicting future diabetes in Latino women with gestational diabetes. Utility of early post- partum glucose tolerance testing. Diabetes 1995;44: For More Information 586–91. (Level II-3) ^ 11. Rosenstein MG, Cheng YW, Snowden JM, Nicholson The American College of Obstetricians and Gynecol- JM, Doss AE, Caughey AB. The risk of stillbirth and ogists has identified additional resources on topics infant death stratified by gestational age in women with related to this document that may be helpful for ob- gestational diabetes. Am J Obstet Gynecol 2012;206:309. gyns, other health care providers, and patients. You e1–7. (Level II-3) ^ may view these resources at www.acog.org/More-Info/ 12. Metzger BE, Lowe LP, Dyer AR, Trimble ER, GestationalDiabetes. Chaovarindr U, Coustan DR, et al. Hyperglycemia and adverse pregnancy outcomes. HAPO Study Cooperative These resources are for information only and are not Research Group. N Engl J Med 2008;358:1991–2002. meant to be comprehensive. Referral to these resources (Level II-3) ^ does not imply the American College of Obstetricians 13. Dabelea D, Hanson RL, Lindsay RS, Pettitt DJ, and Gynecologists’ endorsement of the organization, the Imperatore G, Gabir MM, et al. Intrauterine exposure to organization’s website, or the content of the resource. diabetes conveys risks for type 2 diabetes and obesity: a These resources may change without notice. study of discordant sibships. Diabetes 2000;49:2208–11. (Level II-2) ^ 14. Clausen TD, Mathiesen ER, Hansen T, Pedersen O, Jensen DM, Lauenborg J, et al. Overweight and the References in adult offspring of women with diet-treated gestational diabetes mellitus or type 1 1. 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Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 99. Rouse DJ, Owen J, Goldenberg RL, Cliver SP. The effectiveness and costs of elective cesarean delivery The MEDLINE database, the Cochrane Library, and for fetal macrosomia diagnosed by ultrasound. JAMA ACOG’s own internal resources and documents were used 1996;276:1480–6. (Level II-3) ^ to con­duct a lit­er­a­ture search to lo­cate rel­e­vant ar­ti­cles pub­lished be­tween January 1990 and May 2017. The search 100. Garabedian C, Deruelle P. Delivery (timing, route, was re­strict­ed to ar­ti­cles pub­lished in the English lan­guage. peripartum glycemic control) in women with gestational Pri­or­i­ty was given to articles report­ ­ing results of origi­­nal diabetes mellitus. Diabetes Metab 2010;36:515–21. re­search, although re­view ar­ti­cles and com­men­tar­ies also (Level III) ^ were consulted. Ab­stracts of re­search pre­sent­ed at sym­po­ 101. Fetal macrosomia. Practice Bulletin No. 173. American sia and sci­en­tif­ic con­fer­enc­es were not con­sid­ered adequate College of Obstetricians and Gynecologists. Obstet for in­clu­sion in this doc­u­ment. Guide­lines pub­lished by Gynecol 2016;128:e195–209. (Level III) ^ or­ga­ni­za­tions or in­sti­tu­tions such as the Na­tion­al In­sti­tutes of Health and the Amer­i­can Col­lege of Ob­ste­tri­cians and 102. Kaaja RJ, Greer IA. Manifestations of chronic disease Gy­ne­col­o­gists were re­viewed, and ad­di­tion­al studies were during pregnancy. JAMA 2005;294:2751–7. (Level III) located by review­ ­ing bib­liographies of identified articles. ^ When re­li­able research was not available, expert opinions 103. Buchanan TA, Xiang AH. Gestational diabetes mellitus. from ob­ste­tri­cian–gynecologists were used. J Clin Invest 2005;115:485–91. (Level III) ^ Studies were reviewed and evaluated for qual­i­ty ac­cord­ing 104. Russell MA, Phipps MG, Olson CL, Welch HG, to the method outlined by the U.S. Pre­ven­tive Services Carpenter MW. Rates of postpartum glucose testing Task Force: after gestational diabetes mellitus. Obstet Gynecol I Evidence obtained from at least one prop­erly­ 2006;108:1456–62. (Level II-2) ^ de­signed randomized controlled trial. 105. Chodick G, Elchalal U, Sella T, Heymann AD, Porath A, II-1 Evidence obtained from well-designed controlled­ Kokia E, et al. The risk of overt diabetes mellitus among tri­als without randomization. women with gestational diabetes: a population-based II-2 Evidence obtained from well-designed co­hort or study. Diabet Med 2010;27:779–85. (Level II-3) ^ case–control analytic studies, prefer­ ­a­bly from more than one center or research group. 106. Bellamy L, Casas JP, Hingorani AD, Williams D. Type II-3 Evidence obtained from multiple time series with or 2 diabetes mellitus after gestational diabetes: a system- with­out the intervention. Dramat­ ­ic re­sults in uncon­ ­ atic review and meta-analysis. Lancet 2009;373:1773–9. trolled ex­per­i­ments also could be regarded as this (Meta-analysis) ^ type of ev­i­dence. 107. Metzger BE, Buchanan TA, Coustan DR, de Leiva A, III Opinions of respected authorities, based on clin­i­cal Dunger DB, Hadden DR, et al. Summary and recommen- ex­pe­ri­ence, descriptive stud­ies, or re­ports of ex­pert dations of the Fifth International Workshop-Conference committees. on Gestational Diabetes Mellitus [published erratum Based on the highest level of evidence found in the data, appears in Diabetes Care 2007;30:3154]. Diabetes Care recommendations are provided and grad­ed ac­cord­ing to the 2007;30 Suppl 2:S251–60. (Level III) ^ following categories: Level A—Recommendations are based on good and con­ sis­tent sci­en­tif­ic evidence. Level B—Recommendations are based on limited or in­con­ sis­tent scientific evidence. Level C—Recommendations are based primarily on con­ sen­sus and expert opinion.

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Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.